Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients

Naoko Otani-Takei, Takahiro Masuda, Tetsu Akimoto, Sumiko Honma, Yuko Watanabe, Kazuhiro Shiizaki, Takuya Miki, Eiji Kusano, Yasushi Asano, Makoto Kuro-O, Daisuke Nagata, Naoko Otani-Takei, Takahiro Masuda, Tetsu Akimoto, Sumiko Honma, Yuko Watanabe, Kazuhiro Shiizaki, Takuya Miki, Eiji Kusano, Yasushi Asano, Makoto Kuro-O, Daisuke Nagata

Abstract

Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7 ± 5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309-449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all-cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29-13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality.

Figures

Figure 1
Figure 1
Kaplan-Meier plots of cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c). The patients were categorized into low-KL (

Figure 2

Cardiovascular event-free survival (a), cardiovascular…

Figure 2

Cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c) by the…

Figure 2
Cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c) by the 25th percentile of serum soluble Klotho. Note that the patients categorized into the low-KL (p = 0.047) and cumulative survival (p = 0.005) rates.

Figure 3

Significance of the serum FGF23…

Figure 3

Significance of the serum FGF23 levels with respect to cardiovascular event-free survival (a),…

Figure 3
Significance of the serum FGF23 levels with respect to cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c). The patients were categorized into low-FGF23 (
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Figure 2
Figure 2
Cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c) by the 25th percentile of serum soluble Klotho. Note that the patients categorized into the low-KL (p = 0.047) and cumulative survival (p = 0.005) rates.
Figure 3
Figure 3
Significance of the serum FGF23 levels with respect to cardiovascular event-free survival (a), cardiovascular mortality (b), and cumulative survival (c). The patients were categorized into low-FGF23 (

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